Project Summary Severe asthma accounts for a disproportionate share of the morbidity associated with asthma. Multiple biological therapies are now becoming available that target eosinophilic or Type 2- driven asthma. However, data from SARP indicate that >60% of patients have severe asthma with a neutrophilic phenotype (SANP), as defined by induced sputum differentials. These patients experience excess morbidity, and there are currently no therapies that effectively target neutrophilic inflammation. We recently completed a study wherein we showed that targeting mast cells with imatinib (an inhibitor of stem-cell factor signaling at KIT) was most effective in patients with a neutrophilic phenotype. Further, we found that reductions in serum tryptase could identify patients most likely to respond to this treatment. Additionally, we have shown that in severe asthma, despite aggressive corticosteroid therapy (which normally reduces inflammatory eicosanoids) these patients continue to elaborate pro-inflammatory eicosanoids and low-pro-resolving eicosanoids. This is indicated by our discovery of persistent elevation of LTB4 (which is a potent neutrophil chemoattractant) in exhaled breath condensate. Lastly, IL-6 has been associated with non-Type 2 asthma, insulin resistance, and TH17 skewing of CD4+ cells. IL6 receptor polymorphisms have been associated with asthma risk, and high IL6 has been associated with reduced lung function and increased exacerbations, even in a cohort of severe asthmatics. We posit the following set of primary hypotheses and in each case we list the severe asthma phenotype and its phenotype marker(s) (PM), our primary candidate response marker at 2 months (RM) (in parentheses our secondary RMs), and the targeted intervention (TI). Our hypotheses are that in subjects with : 1) SANP with high serum IL6 (PM), a fall in?C-reactive protein (TH17 cells, insulin resistance ) (RM), will identify those more likely to improve after anti-IL6 therapy (TI); 2) SANP with high exhaled LTB4 (PM), a fall in exhaled LTB4 (urinary cysteinyl leukotrienes) (RM) will identify those more likely to improve with a 5- lipoxygenase inhibitor (5-LOi) (that blocks production of pro-inflammatory eicosanoids); 3) Severe asthma with increased sputum neutrophils (PM), a fall in serum tryptase (sputum supernatant tryptase) (RM) will identify asthmatics more likely to improve after treatment with a KIT inhibitor (TI). Our adaptive study design and treatment approach will allow us to define the threshold values of our RM that identify patients with a higher likelihood of response to targeted therapy. We have a team of seasoned trialists in adult and pediatric asthma, experts in biomarker development, the mechanisms behind these biomarkers, and adaptive trial design and integrative analyses, which will add significant strength to a PRECISE network.